Osteoarthritis (OA) is a group of overlapping distinct diseases, which may have different etiologies but similar biologic, morphologic, and clinical outcomes. The disease process not only affects the articular cartilage, but involves the entire joint, including the subchondral bone, ligaments, capsule, synovial membrane, and periarticular muscles. Ultimately, the articular cartilage degenerates with fibrillation, fissures, ulceration, and full thickness loss of the joint surface. This condition is characterised by focal areas of loss of articular cartilage within synovial joints, associated with hypertrophy of bone (osteophytes and subchondral bone sclerosis) and thickening of the capsule. It may be interpreted as the reaction of synovial joints to injury. This phenomenon can occur in any joint, but is most common in selected joints of the hand, spine, knee, foot and hip. This pathological change, when severe, results in radiological changes (loss of joint space and osteophytes), which have been used in epidemiological studies to estimate the prevalence of OA at different joint sites. The molecular and cellular mechanisms at the basis of the onset of OA are, at present, unknown; it is hypothesised that abnormal load as well as trauma may have a role, but it seems certain that genetics and heritable factors are also involved. Inflammation, when present, is only secondary to a primary event. OA is the most common form of arthritis. The World Health Organization (WHO) estimates that, worldwide, 9.6% of men and 18% of women aged over 60 years have symptomatic OA, classifying OA as the 4th cause of disability in women and the 8th cause in men. It is considered that the risk of disability is the same for knee OA as for cardiac disease. Ultimately OA, due to the underlying process, which consists of an imbalance in cartilage matrix synthesis and breakdown, leading to the destruction of the articular cartilage, results in restricted joint movement, joint instability, pain and chronic disability.
While symptoms, in particular pain, can be controlled by a series of analgesic compounds (from paracetamol to NSAIDS, from opiate to NGF antagonists), it is know that none of these drugs are able to slow the disease progression. On the contrary, strong analgesic compounds could even worsen the underlying pathology (Caso di NGF). What is needed in the art are alternative or supplemental therapies, able of modifying the progressive destruction of cartilage that lastly will conduce to surgical joint replacement.
FYN is acytoplasmatic tyrosine kinase belonging to the Src family kinases that consists of 11 members in humans, including Blk, Brk, Fgr, Frk, Hck, Lck, Lyn, c-Src, Srm and c-Yes (Manning, G. et al., Science, 2002, 298, 1912). FYN has been identified and characterised in 1988 both in normal and transformed cells (Kypta, R. M. et al., EMBO J., 1988, 7, 3837-3844). It is primarily localised to the cytoplasmatic side of the plasma membrane, where it phosphorylates tyrosine residues of enzymes involved in different signalling pathways and works downstream of several cell-surface receptors.
A number of biological functions in which FYN activity is involved has been reported and includes growth factor and cytokine receptor signalling, ion channel function, platelet activation, T cell and B-cell receptor signalling, axon guidance, entry into mitosis, differentiation of natural killer cells, as extensively reported in a recent and complete review (Saito, Y. Et al., Cancer, 2010, 116, 1629).
FYN is primarily involved in several transduction pathways in the central nervous system (CNS) and in the peripheral immune system, playing in this latter important roles in regulation and functions of T-cell development and activation.
FYN overexpression induces morphogenic transformation, alteration of mitogenic signals and stimulation of cell growth and proliferation. FYN is also known to mediate integrin adhesion and cell-cell interactions. For all these reasons, FYN is involved in the onset of cancer (Kawakami T, Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 3870).
For a summary of FYN activity and the status of FYN specific inhibitors a review has been published by Schenone S. on Current Medicinal Chemistry, 2011, 18, 2921.
In the publication Erin F Dimaro et al: “Structure-Guided Design of Aminopyrimidine Amides as Potent, Selective Inhibitors of Lymphocyte Specific Kinase:Synthesis, Structure-Activity Relationships, and Inhibition of in Vivo T Cell Activation” Journal of Medicinal Chemistry, American Chemical Society, vol 51, no. 6, Mar. 1, 2008, pages 1681-1694, Fyn-kinases inhibitors having structure of Aminopyrimidine amides are described.
Then, it is an object of the present invention, to provide FYN kinase inhibitors.